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By Ujwani Nukala

There is an urgent need for compounds that can be used to protect people in case of accidental or terrorist initiated radiological emergencies. Developing compounds that are effective, nontoxic, inexpensive, easy to administer, and capable of being stored for rapid distribution among victims of radiological accidents or attacks, is a pressing but daunting endeavor. In this regard, vitamin E may be the answer. As a well-known antioxidant, vitamin E is effective in scavenging free radicals generated by radiation exposure.

Naturally occurring vitamin E analogs, collectively known as tocols, including eight isoforms, four tocopherols (α, β, γ and δ) and four tocotrienols (α, β, γ and δ), have been investigated as radioprotectors. These studies have shown tocotrienols to possess superior antioxidant property, but despite their very significant radio protective activity, tocotrienols get eliminated from the human body very rapidly. So very large doses or multiple dosing are required to achieve the necessary therapeutic benefits. Their very rapid elimination is due to their low affinity for the protein that is responsible for retaining them in the body, the α-tocopherol transfer protein (ATTP).

In our laboratory, we have designed a new form of vitamin E analogs, the tocoflexols, with enhanced flexibility. These compounds were designed by a rigorous computer-based screening to identify the compounds with highest potential to bind to ATTP, and thus stay longer in the body while maintaining the radioprotectant activity of the tocotrienols. A feasible synthetic procedure, using readily available and relatively inexpensive naturally occurring tocotrienol-containing oils, was used to produce α, γ, and δ-tocoflexols in our laboratory.

Tocoflexol in the binding pocket of ATTP.

The potential of the tocols as clinically useful radioprotectants depends on three distinct factors: their intrinsic level of bioactivity, their ability to penetrate the cells, and their bioavailability. Although, some of the current tocols have good levels of intrinsic bioactivity, their very limited bioavailability has hampered their clinical usefulness. We have designed tocoflexols using computational techniques, which showed that tocoflexols can attain the conformation required for the binding to ATTP and they have been synthesized. The levels of cellular uptake of tocoflexols compared to tocotrienols were evaluated, using mouse NSC-34 cell line as a model for cell-uptake. To determine the anti-oxidant potential of these novel tocoflexols, a TBARS assay was performed to evaluate the ability of the tocoflexols to inhibit lipid peroxidation in microsomes.

Cellular uptake study and TBARS assay have shown that tocoflexols have greater antioxidant potential and greater cellular uptake levels than tocopherols and are comparable to those of tocotrienols, the most potent tocols currently available. Thus, these novel tocotrienol analogs have the potential to be developed as new therapeutics for use in radiological accidents or attacks, and may also be useful for patients undergoing radiotherapy.

Ujwani Nukala is a third year Ph.D. student in Bioinformatics at University of Arkansas for Medical Sciences. Under the mentorship of Dr. Cesar Compadre, Ujwani is working on her dissertation entitled “Design and Development of Novel Vitamin E analogs, Tocoflexols as Radiation Protectors.”